Chronic Myelogenous Leukemia
Conditions
Keywords
First line treatment, newly diagnosed, Philadelphia chromosome positive, Chronic Myelogenous Leukemia, Ph+, CML-CP, major molecular response, Social risk
Brief summary
The study was a local multicentric, open-label, non-randomized phase II study of nilotinib as a first line treatment in adult patients with newly-diagnosed Philadelphia chromosome-positive (Ph+) and chronic phase myeloid leukemia (CML-CP).
Detailed description
This was a multicenter, open-label, single-arm, phase 2 study of nilotinib as a frontline treatment for patients with Ph+ CMLCP. All patients received oral nilotinib 300 mg twice daily for a planned treatment duration of 24 months or until early discontinuation. The primary efficacy end point was the cumulative rate of Major Molecular Response (MMR) in all participants by 12 months. Secondary efficacy end points included the rate of Complete Cytogenic Response (CCyR) at 6 and 12 months; cumulative rates of MMR up to 24 months; time to and durability of MMR; and cumulative rate of Complete Haematologic Response (CHR) by 12 months. Patient evaluations, including hematologic assessments, were conducted every 15 days during the first 3 months, monthly until month 12, and then every 3 months until the end of the study (24 months). All efficacy analyses were performed in the intent-to treat population.
Interventions
DRUGNilotinib
administered orally at a dose of 300 mg twice daily for 24 months
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 * First cytogenetic diagnosis of CML-CP with cytogenetic confirmation of Philadelphia chromosome of (9;22) translocations within 6 months. Standard conventional cytogenetic analysis must be performed. * Previously untreated for CML, except for hydroxyurea and/or anagrelide (except imatinib treatment for max. 31 days long) * Adequate end organ function with following laboratory criteria: total bilirubin \< 1.5 x upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 2.5 x upper limit of normal (ULN); creatinine \< 1.5 x upper limit of normal (ULN); serum amylase and lipase ≤ 1.5 x upper limit of normal (ULN); alkaline phosphatase ≤ 2.5 x upper limit of normal (ULN) unless considered tumor related * Serum potassium, magnesium, and phosphorus levels are equal or above the lower limit of normal prior to the first dose of study medication
Exclusion criteria
* Treatment with tyrosine kinase inhibitor(s) prior to study (in emergent cases where the patient requires disease management while awaiting study start, commercial supplies of imatinib at any dose may be prescribed to the patient but for no longer than 31 days in duration) * Known cytopathologically confirmed Central Nervous System CNS infiltration * Impaired cardiac function * Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection) * Acute or chronic liver, pancreatic or severe renal disease considered unrelated to disease * Patients with another primary malignancy except if the other primary malignancy is neither currently clinically significant or requiring active intervention * History of significant congenital or acquired bleeding disorder unrelated to cancer * Previous radiotherapy to ≥25% of the bone marrow * Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery) * Use of therapeutic coumarin derivatives (i.e. warfarin, acenocoumarol, phenprocoumon) * Patients actively receiving therapy with strong Cytochrome P450 3A4 isoenzyme (CYP3A4) inhibitors (e.g, erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) * Patients actively receiving therapy with medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Major Molecular Response (MMR) During the First 12 Months | 12 months | Major Molecular Response (MMR) was defined as BCR-ABL1\^IS ≤0.1%, on the International Scale \[BCR-ABL1IS\]) by 12 months. BCR is the Breakpoint Cluster Region gene / BCR gene product and ABL is the Abelson proto-oncogene. BCR-ABL is the Fusion gene from BCR and ABL/Protein product from BCR-ABL. Participants who withdrew prematurely or those who failed to provide data for the study for other reasons were designated as premature withdrawal or inevaluable, respectively, and were included in the ITT analysis as non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Major Molecular Response (MMR) up to 24 Months | 3, 6, 9, 15, 18, 21 and 24 months | Major Molecular Response (MMR) was defined as BCR-ABL1\^IS ≤0.1%, on the International Scale \[BCR-ABL1IS\]) by 12 months. BCR is the Breakpoint Cluster Region gene / BCR gene product and ABL is the Abelson proto-oncogene. BCR-ABL is the Fusion gene from BCR and ABL/Protein product from BCR-ABL. Participants who withdrew prematurely or those who failed to provide data for the study for other reasons were designated as premature withdrawal or inevaluable, respectively, and were included in the ITT analysis as non-responders. |
| Percentage of Participants With Complete Cytogenetic Response (CCyR) at Month 6 and 12 | Month 6 and 12 | CCyR rate is identified as the rate of patients who had 0% of Ph+ metaphase. |
| Percentage of Participants With Complete Hematologic Response (CHR) at Month 3, 6, 9, 12, 18 and 24 | Month 3, 6, 9, 12, 18 and 24 | A confirmed complete hematological response (CHR) is defined when all of the following criteria are achieved: WBC \<10 x 109/L, thrombocyte \<450 x 109/L, myelocyte + metamyelocyte \<%5 in blood, no sign of blast and promyelocyte in blood, basophil \<%5, and no sign of extramedullary involvement. |
| Time to Major Molecular Response (MMR) | 24 months | Time to MMR is defined as the time period from the date of first dose intake until the first documented MMR. |
| Duration of Major Molecular Response (MMR) | 24 months | MMR duration is defined as the time from the date of first documented MMR to the first time of the lost MMR, progression or death. |
Countries
Turkey (Türkiye)
Participant flow
Recruitment details
A total of 112 participants were enrolled into the study from the 15 sites in Turkey.
Pre-assignment details
This was an open-label study with one treatment arm. The study did not involve a reference treatment.
Participants by arm
| Arm | Count |
|---|---|
| Nilotinib administered orally at a dose of 300 mg twice daily for 24 months | 112 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 8 |
| Overall Study | Death | 2 |
| Overall Study | hospitalization | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | patient not compliant with the protocol | 1 |
| Overall Study | Pregnancy | 1 |
| Overall Study | progression of disease | 3 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Nilotinib | — |
|---|---|---|
| Age, Continuous | 47 years | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 49 Participants | — |
| Sex: Female, Male Male | 63 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 112 |
| other Total, other adverse events | 90 / 112 |
| serious Total, serious adverse events | 43 / 112 |
Outcome results
Primary
Percentage of Participants Who Achieved Major Molecular Response (MMR) During the First 12 Months
Major Molecular Response (MMR) was defined as BCR-ABL1\^IS ≤0.1%, on the International Scale \[BCR-ABL1IS\]) by 12 months. BCR is the Breakpoint Cluster Region gene / BCR gene product and ABL is the Abelson proto-oncogene. BCR-ABL is the Fusion gene from BCR and ABL/Protein product from BCR-ABL. Participants who withdrew prematurely or those who failed to provide data for the study for other reasons were designated as premature withdrawal or inevaluable, respectively, and were included in the ITT analysis as non-responders.
Time frame: 12 months
Population: Intent-to-treat (ITT) analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nilotinib | Percentage of Participants Who Achieved Major Molecular Response (MMR) During the First 12 Months | 74 Participants |
Secondary
Duration of Major Molecular Response (MMR)
MMR duration is defined as the time from the date of first documented MMR to the first time of the lost MMR, progression or death.
Time frame: 24 months
Population: ITT analysis set. Only participants with a MMR and subsequent loss of MMR were included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nilotinib | Duration of Major Molecular Response (MMR) | 91 days | Standard Deviation 4.22 |
Secondary
Percentage of Participants Who Achieved Major Molecular Response (MMR) up to 24 Months
Major Molecular Response (MMR) was defined as BCR-ABL1\^IS ≤0.1%, on the International Scale \[BCR-ABL1IS\]) by 12 months. BCR is the Breakpoint Cluster Region gene / BCR gene product and ABL is the Abelson proto-oncogene. BCR-ABL is the Fusion gene from BCR and ABL/Protein product from BCR-ABL. Participants who withdrew prematurely or those who failed to provide data for the study for other reasons were designated as premature withdrawal or inevaluable, respectively, and were included in the ITT analysis as non-responders.
Time frame: 3, 6, 9, 15, 18, 21 and 24 months
Population: ITT analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nilotinib | Percentage of Participants Who Achieved Major Molecular Response (MMR) up to 24 Months | 3 months | 28 Participants |
| Nilotinib | Percentage of Participants Who Achieved Major Molecular Response (MMR) up to 24 Months | 6 months | 57 Participants |
| Nilotinib | Percentage of Participants Who Achieved Major Molecular Response (MMR) up to 24 Months | 9 months | 67 Participants |
| Nilotinib | Percentage of Participants Who Achieved Major Molecular Response (MMR) up to 24 Months | 15 months | 84 Participants |
| Nilotinib | Percentage of Participants Who Achieved Major Molecular Response (MMR) up to 24 Months | 18 months | 92 Participants |
| Nilotinib | Percentage of Participants Who Achieved Major Molecular Response (MMR) up to 24 Months | 21 months | 93 Participants |
| Nilotinib | Percentage of Participants Who Achieved Major Molecular Response (MMR) up to 24 Months | 24 months | 93 Participants |
Secondary
Percentage of Participants With Complete Cytogenetic Response (CCyR) at Month 6 and 12
CCyR rate is identified as the rate of patients who had 0% of Ph+ metaphase.
Time frame: Month 6 and 12
Population: ITT analysis set included only the participants who had measurements i.e. excluding drop outs.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nilotinib | Percentage of Participants With Complete Cytogenetic Response (CCyR) at Month 6 and 12 | Month 6 | 89 Participants |
| Nilotinib | Percentage of Participants With Complete Cytogenetic Response (CCyR) at Month 6 and 12 | Month 12 | 84 Participants |
Secondary
Percentage of Participants With Complete Hematologic Response (CHR) at Month 3, 6, 9, 12, 18 and 24
A confirmed complete hematological response (CHR) is defined when all of the following criteria are achieved: WBC \<10 x 109/L, thrombocyte \<450 x 109/L, myelocyte + metamyelocyte \<%5 in blood, no sign of blast and promyelocyte in blood, basophil \<%5, and no sign of extramedullary involvement.
Time frame: Month 3, 6, 9, 12, 18 and 24
Population: ITT analysis set included only the participants who had measurements i.e. excluding drop outs.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nilotinib | Percentage of Participants With Complete Hematologic Response (CHR) at Month 3, 6, 9, 12, 18 and 24 | Month 3 | 104 Participants |
| Nilotinib | Percentage of Participants With Complete Hematologic Response (CHR) at Month 3, 6, 9, 12, 18 and 24 | Month 6 | 102 Participants |
| Nilotinib | Percentage of Participants With Complete Hematologic Response (CHR) at Month 3, 6, 9, 12, 18 and 24 | Month 9 | 100 Participants |
| Nilotinib | Percentage of Participants With Complete Hematologic Response (CHR) at Month 3, 6, 9, 12, 18 and 24 | Month 12 | 96 Participants |
| Nilotinib | Percentage of Participants With Complete Hematologic Response (CHR) at Month 3, 6, 9, 12, 18 and 24 | Month 18 | 93 Participants |
| Nilotinib | Percentage of Participants With Complete Hematologic Response (CHR) at Month 3, 6, 9, 12, 18 and 24 | Month 24 | 92 Participants |
Secondary
Time to Major Molecular Response (MMR)
Time to MMR is defined as the time period from the date of first dose intake until the first documented MMR.
Time frame: 24 months
Population: ITT analysis set. Only participants with a MMR were included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nilotinib | Time to Major Molecular Response (MMR) | 252.38 days | Standard Deviation 153.22 |